Epothilones are a class of macrocyclic lactones that were originally isolated from myxobacterium Sorangium Cellulosum3. They are potent antitumor agents whose activity is akin to that of taxol derivatives, but with better efficacy and milder side effects. Like Taxols, Epothilones elicit antitumor effect by inhibiting microtubule function thereby preventing mitosis (cell division). To date, six Epothilone (‘Epo’) derivatives (Epo A-F) have been identified, and all of them possess the macrocyclic 16-membered ring lactone core. Due to their remarkable antitumor property, Epothilones have attracted considerable attention, and hundreds of articles related to the structure, synthesis, and biological activities of both natural and synthetic Epothilones have been published. Danishefsky et al. reported the first total synthesis of Epo A in 1996 and of Epo B-F subsequently.4 Since then, many other groups have attempted to develop efficient and commercially viable synthetic methods for both the natural products as well the synthetic analogs. Several synthetic analogs are undergoing clinical trials, and one of the analogs, Ixabepilone (I) (the active pharmaceutical ingredient (API) in IXEMPRA™) displays greater metabolic stability than its precursor, and has been approved by FDA for the treatment of metastatic breast cancer. Ixabepilone (‘Ixa’) is the lactam analog of Epo B (II), and is currently being synthesized from II. The total synthesis of Epo B (2), which is the key intermediate in the synthesis of Ixa, was achieved earlier by Danishefsky et al.,5 and more recently by Wang et al.6 The conversion of Epo B to Ixabepilone has been reported by Kim et al.,7 which is hereby incorporated by reference in its entirety.
All the prior art methods for the production of Epo B and Ixa fall into two general approaches: fermentation and total synthesis. Both are best with two major problems. The major problem with the fermentation approach is the lack of control of the biosynthesis of Epo B, which results in the formation of a complex mixture of products that warrants an elaborate and tedious process for the isolation and purification of II. This, in turn, has a considerable impact on the overall yield. On the other hand, the total synthesis approach has consistently been suffering from poor scalability and yields. Nevertheless, the synthetic approach offers important advantages over the fermentation process in that the former offers a potentially better “scalability” prospect and superior control over side reactions, which both are important factors in having a reproducible process and reliable impurity profiles at each step. Accordingly, the objective of the present invention is to develop an efficient, practical, and totally synthetic process of Epo B (I) and transform it to its lactam analog, Ixa (II), at a manufacturing scale.